KR20150013124A - N-methyl-4-benzylcarbamidopyridinium chloride and a process for its preparation - Google Patents

Abstract

The present invention relates to novel salts of N-methyl-4-benzylcarbamidopyridines, their preparation, pharmaceutical compositions comprising them and their use for the treatment or prevention of viral diseases.

Description

N-METHYL-4-BENZYLCARBAMIDOPYRIDINIUM CHLORIDE AND A PROCESS FOR ITS PREPARATION BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to N-

The present invention relates to a process for the preparation of N-methyl-4-benzylcarbamidopyridinium chloride, to a compound obtained by the process, to a pharmaceutical composition comprising the compound and to its use in the treatment or prevention of viral diseases .

N-methyl-4-benzylcarbamidopyridinium chloride (also referred to herein as "FAV00A-Cl") is N-methyl-4-benzylcarbamidopyridinium iodide (also referred to herein as "FAV00A-Io" ) Amizon < / RTI > The pharmaceutically acceptable salts of carbabenzpyride have valuable pharmacological properties.

Its principal characteristics are the treatment and prevention of viral infections, more specifically infections caused by influenza A virus.

For pharmaceutical uses, it is of primary interest to have very pure materials. It is also advisable to use a stable, strong, and scalable industrial process to produce a highly consistent quality of product that should be compatible with pharmaceutical formulations.

Description of Prior Art

Amizone is described, for example, in SU 58612 (1975), which describes the synthesis of carbamazepyridines for pharmaceutical purposes, but the method of obtaining the drug in a reproducible manner is not fully described in this document have.

Amizon is described in Nesterova et al .: " Studying of Anti-Epstein-Barr Virus Activity of Amizon and Their Derivative ", ANTIVIRAL RESEARCH, ELSE-VIER BV, NL, Vol. 78, No. 2, 19 March 2008, page A61; XP022541825 and Bu-khtiarova T. A. et al .: "Structure and antiinflammatory activity of isonicotinic and nicotinic amides", PHARMACEUTICAL CHEMISTRY JOURNAL, SPRINGER NEW YORK LLC, US, Vol. 31, No. 11, 1 January 1997, pages 597-599.

Also, in these documents, aminzon is described only in an undefined form.

The novel morphological form, i.e. the a-crystalline form of the amidos, is described in the co-pending patent applications WO < RTI ID = 0.0 > 2011/158058 < / RTI > Although the novel morphological form exhibits a better dissolution profile compared to the above-described prior art forms of amidines, its release profile is still improved in an attempt to provide a rapid dissolution dosage form There is a need.

Accordingly, there is provided a novel salt of N-methyl-4-benzylcarbamidopyridine having an improved release profile as compared to the above-mentioned prior art forms of N-methyl-4-benzylcarbamopopyridinium iodide Is a technical problem on which the present invention is based.

The above object is achieved by a process for the preparation of a novel salt, namely N-methyl-4-benzylcarbamate, by a process comprising quaternizing a pyridinium ring atom of isonicotinic acid benzylamide with chloromethane according to the following reaction: ≪ / RTI > is achieved by providing the chloride salt of pyridine:

Figure 1 shows a plot of N-methyl-4-benzylcarboxamidopyridinium chloride from a crystal structure showing the numbering scheme used. Anisotropic atomic displacement ellipsoids for non-hydrogen atoms appear at a 50% probability level. Hydrogen atoms with arbitrarily small radii are visible.
Figures 2, 4 and 6 show the release profiles of N-methyl-4-benzylcarbamamidopyridinium chloride contained in the capsules in an amount of 370.6 mg.
Figures 3, 5 and 7 show the dissolution profile of both capsules containing the above-mentioned N-methyl-4-benzyl carbamidopyridinium chloride capsules and the corresponding iodide salt in an amount of 500 mg.

As mentioned above, in accordance with a first aspect, the present invention provides a process for the preparation of N-methyl-4-benzylcarbamidopia, comprising the step of quaternizing a pyridinium ring atom of a isonicotinic acid benzylamide with chloromethane according to the following scheme: Lt; / RTI > chloride.

The reaction can be carried out in various organic solvents. Preferably polar solvents selected from 2-propanol, aqueous ethanol and acetonitrile are used.

In addition to the above-mentioned polar solvents, acetone and alcohols other than ethanol may be mentioned.

According to a preferred embodiment of the present invention, aqueous ethanol containing water in an amount of 1 to 20% is used as a polar solvent.

The reaction of the components in 96% ethanol is most suitable for the production of industrial scale FAV00A-Cl. 96% ethanol is a cheaper solvent compared to 2-propanol and acetonitrile and is less toxic. In addition, the reaction in 96% ethanol was carried out using a small amount of chloromethane (1.5 mol of chloromethane per 1 mol of isonicotinic acid benzylamide) compared with 2-propanol (2 mol of chloromethane per 1 mol of isonicotinic acid benzylamide) at low pressure compared to acetonitrile . The FAV00A-Cl material resulting from the reaction in 96% ethanol is relatively pure with respect to the technology grade product - the admixture is no more than 0.5% and the yield of the reaction is relatively high, i.e. about 80%.

Generally, the reaction between isonicotinic acid benzylamide and chloromethane is carried out in a temperature range of 50 to 120 캜, preferably 80 to 100 캜.

Typically, the reaction is carried out in an autoclave under a pressure ranging from 0.1 to 1 MPa (1 to 10 bar), but N-methyl-4-benzylcarbamidopyridinium chloride can also be prepared according to the invention have. In this case, the reaction is preferably carried out by continuously passing chloromethane gas through the reaction mixture without any pressure while heating in acetonitrile, i.e. the reaction is carried out at atmospheric or atmospheric pressure.

The reaction time is usually in the range of 1 to 20 hours, preferably 12 to 16 hours.

The molar ratio between isonicotinic acid benzylamide and chloromethane is usually in the range of 1 to 2, preferably 1 to 1.5, depending on the solvent used. As mentioned above, a small amount of chloromethane (1.5 mol of chloromethane per 1 mol of isonicotinic acid benzylamide) is used for 96% ethanol compared to 2-propanol (2 mol of chloromethane per 1 mol of isonicotinic acid benzylamide) .

The N-methyl-4-benzylcarbamamidopyridinium chloride produced by the reaction with chloromethane can be further purified, preferably by recrystallization from 96% ethanol. By doing so, a final product with an impurity level of less than 0.5% can be obtained. In particular, N-methyl-4-benzylcarbamidopyridinium chloride having less than 0.05% isonicotinic acid benzylamide can be obtained.

Depending on the level of impurities contained in the N-methyl-4-benzylcarbamidopyridinium chloride, its melting point is in the range of 193 to 205 占 폚. The purest product obtained in the examples shown below has a sharp melting point in the range of 198 to 203 占 폚.

Finally, the present invention relates to a pharmaceutical composition comprising a novel salt form, i.e. a chloride form, of N-methyl-4-benzylcarbamidopyridine.

The composition may be in the form of a capsule containing the active ingredient in an amount of 0.01 to 100% by weight.

Such pharmaceutical compositions are useful for the treatment or prevention of viral diseases. Such viral diseases include influenza-like diseases caused by influenza and respiratory virus infections.

The present invention is further illustrated by the following examples and comparative examples.

Experimental part

Example 1. 260 ml of 2-propanol was cooled in a glass flask to 2-4 占 폚. 30.5 g (0.6 M) of chloromethane was dissolved at this temperature. 64 g (0.3 M) of isonicotinic acid benzylamide, 90 ml of cooled 2-propanol and a 2-propanol solution saturated with chloromethane were placed in an autoclave. The autoclave was closed and heated to 100 < 0 > C. The mixture was allowed to react at this temperature for 5 hours. The mixture was then cooled to room temperature itself. The reaction mixture was transferred to a glass flask and cooled to 0-2 < 0 > C. The precipitate was filtered off and washed with 60 ml of 2-propanol cooled on the filter. The precipitate was dried at room temperature for 24 hours. Production - 74 g (95% yield based on isonicotinic acid benzylamide).

Analysis parameters:

Assay - 99.17%

Impurity - isonicotinic acid benzylamide - 0.8%

Melting point - 196.3 - 200.7 캜

Example 2. 500 ml of 96% ethanol was cooled to 2 to 4 占 폚 in a glass flask. 65 g (1.29 M) of chloromethane was dissolved at this temperature. 181.91 g (0.86 M) of isonicotinic acid benzylamide and 96% ethanol solution saturated with chloromethane were placed in an autoclave. The autoclave was closed and heated to 100 < 0 > C. The mixture was allowed to react at this temperature for 5 hours. The mixture was then cooled to room temperature by itself. The reaction mixture was transferred to a glass flask and cooled to 0-2 < 0 > C. The precipitate was filtered off and washed with 50 ml of 96% ethanol cooled on the filter. The precipitate was dried at room temperature for 24 hours. Yield - 182.2 g (81% yield based on isonicotinic acid benzylamide).

Analysis parameters:

Assay - 99.2%

Impurity - isonicotinic acid benzylamide - 0.5%

Melting point - 200.9 - 201.3 캜

Example 3. 260 ml of acetonitrile were cooled in a glass flask to 2-4 占 폚. 43.91 g (0.87 M) of chloromethane was dissolved at this temperature. 122.89 g (0.58 M) of isonicotinic acid benzylamide, 300 ml of cooled acetonitrile and an acetonitrile solution saturated with chloromethane were placed in an autoclave. The autoclave was closed and heated to 100 < 0 > C. The mixture was allowed to react at this temperature for 3 hours. The mixture was then cooled to room temperature by itself. The reaction mixture was transferred to a glass flask and cooled to 0-2 < 0 > C. The precipitate was filtered off and washed with 100 ml of acetonitrile cooled on the filter. The precipitate was dried at room temperature for 24 hours. Yield - 113 g (yield included in 75% based on isonicotinic acid benzylamide).

Analysis parameters:

Assay - 100.7%

Impurity - isonicotinic acid benzylamide - 0.07%

Melting point - 187.4 - 201.4 캜

Example 4. 210 ml of 96% ethanol was cooled to 2 to 4 占 폚 in a glass flask. 28.86 g (0.57 M) of chloromethane was dissolved at this temperature. 80.78 g (0.28 M) of isonicotinic acid benzylamide and 96% ethanol solution saturated with chloromethane were placed in an autoclave. The autoclave was closed and heated to 100 < 0 > C. The mixture was allowed to react at this temperature for 4 hours. The mixture was then cooled to room temperature by itself. The reaction mixture was transferred to a glass flask and cooled to 0-2 < 0 > C. The precipitate was filtered off and washed with 40 ml of 96% ethanol cooled on the filter. The precipitate was dried at room temperature for 24 hours. Yield - 71.1 g (72% yield based on isonicotinic acid benzylamide).

Analysis parameters:

Assay - 97.74%

Impurity - isonicotinic acid benzylamide - 0.5%

Melting point - 201.4 ℃

Example 5. 260 ml of 96% ethanol was cooled to 2 to 4 占 폚 in a glass flask. 37.45 g (0.74 M) of chloromethane was dissolved at this temperature. 104.8 g (0.49 M) of isonicotinic acid benzylamide and 96% ethanol solution saturated with chloromethane were placed in an autoclave. The autoclave was closed and heated to 100 < 0 > C. The mixture was allowed to react at this temperature for 5 hours. The mixture was then cooled to room temperature by itself. The reaction mixture was transferred to a glass flask and cooled to 0-2 < 0 > C. The precipitate was filtered off and washed with 30 ml of 96% ethanol cooled on the filter. The precipitate was dried at room temperature for 24 hours. Yield - 105.27 g (82% yield based on isonicotinic acid benzylamide).

Analysis parameters:

Assay - 99.2%

Impurity - isonicotinic acid benzylamide - 0.5%

Melting point - 201.1 ℃

Example 6. 540 ml of 96% ethanol was cooled to 2 to 4 占 폚 in a glass flask. 70 g (1.37 M) of chloromethane was dissolved at this temperature. 196 g (0.92 M) of isonicotinic acid benzylamide and 96% ethanol solution saturated with chloromethane were placed in an autoclave. The autoclave was closed and heated to 100 < 0 > C. The mixture was allowed to react at this temperature for 7 hours. The mixture was then cooled to room temperature by itself. The reaction mixture was transferred to a glass flask and cooled to 0-2 < 0 > C. The precipitate was filtered off and washed with 70 ml of 96% ethanol cooled on the filter. The precipitate was dried at room temperature for 24 hours. Yield - 193.5 g (79% yield based on isonicotinic acid benzylamide).

Analysis parameters:

Assay - 91.1%

Impurity - isonicotinic acid benzylamide - 0.5%

Melting point - 201.3 ℃

Example 7. 30 g of technical grade FAV00A-Cl, 45 ml of 96% ethanol and 0.45 g of activated charcoal were placed in a glass flask. The mixture was heated to boiling and allowed to react for 30 minutes. Activated carbon was filtered. The solution was allowed to cool itself to room temperature. Subsequently, it was cooled to 0 - 2 캜 and reacted at this temperature for 3 hours. The precipitate was filtered off and washed with 10 ml of 96% ethanol cooled on the filter. The precipitate was dried at room temperature for 24 hours. Yield - 26.12 g (yield included 87% based on technical grade FAV00A-Cl).

Analysis parameters:

Assay - 101.18%

Impurity - isonicotinic acid benzylamide - 0.12%

Melting point - 201.4 ℃

Example 8. 117.93 g of technical grade FAV00A-Cl, 205.5 ml of 96% ethanol and 2 g of activated carbon were placed in a glass flask. The mixture was heated to boiling and allowed to react for 30 minutes. Activated carbon was filtered. The solution was allowed to cool itself to room temperature. Subsequently, it was cooled to 0 - 2 캜 and reacted at this temperature for 3 hours. The precipitate was filtered off and washed with 40 ml of 96% ethanol cooled on the filter. The precipitate was dried at room temperature for 24 hours. Yield - 94.6 g (yield included in technical grade FAV00A-Cl 80%).

Analysis parameters:

Assay - 99.21%

Impurity - isonicotinic acid benzylamide - 0.2%

Melting point - 199.6 ℃

Example 9 547.5 g of technical grade FAV00A-Cl, 925 ml of 96% ethanol and 9.25 g of activated carbon were placed in a glass flask. The mixture was heated to boiling and allowed to react for 30 minutes. Activated carbon was filtered. The solution was allowed to cool itself to room temperature. Subsequently, it was cooled to 0 - 2 캜 and reacted at this temperature for 3 hours. The precipitate was filtered off and washed with 150 ml of 96% ethanol cooled on the filter. The precipitate was dried at room temperature for 24 hours. Production - 433 g (yield included 79% based on technical grade FAV00A-Cl).

Analysis parameters:

Assay - 100.44%

Impurity - isonicotinic acid benzylamide - 0.02%

Melting point - 198.9 ℃

The present inventors have also developed a method for producing FAV00A-Cl without pressurization. The reaction is carried out in acetonitrile with continued passage of the chloromethane gas to the reaction mixture while heating.

Example 10. 200 ml of acetonitrile and 42.26 g of isonicotinic acid benzylamide were placed in a glass flask. The mixture was heated to 60 < 0 > C. The chloromethane gas was continuously passed through the reaction mixture at this temperature for 10 hours. The solution was allowed to cool itself to room temperature. Subsequently, it was cooled to 0 - 2 캜 and reacted at this temperature for 3 hours. The precipitate was filtered off and washed with 40 ml of acetonitrile cooled on the filter. The precipitate was dried at room temperature for 24 hours. Yield - 18.1 g (35% yield based on isonicotinic acid benzylamide).

Analysis parameters:

Assay - 100.6%

Impurity - isonicotinic acid benzylamide - 0.02%

Melting point - 200 - 202.1 DEG C

Next, one sample of N-methyl-4-benzylcarbamidopyridinium chloride (hereinafter referred to as "sample No. 2") prepared in the above-mentioned example was taken and crystal structure information for this compound was obtained .

The final cell constant is shown below:

a = 14.5489 (5) Å, b = 5.7837 (2) Å, c = 17.0030 (6) Å, α = 90 °, β = 114.935 (2) °, γ = 90 °, volume = 1297.38 (8) Å ³ . Final Residue: R1 [for 2481 I > 2σ ( I )] = 3.10% wR2 [for all 2984 data] = 8.28%.

Experiment information for sample No. 2

A white prism of C ₁₄ H ₁₅ IN ₂ O with approximate dimensions of 0.10 mm x 0.10 mm x 0.10 mm was used for X-ray crystallographic analysis. X-ray intensity data were recorded at 100 (2) K on a Bruker SMART APEX II system equipped with a graphite monochromator and a MoKα pin-focus sealing tube (λ = 0.71073Å) operated at 1250 W power (50 kV, 25 mA) Respectively. The detector was placed at a distance of 40 mm from the crystal. 691 frames were recovered at a scan width of 0.75 °. All frames were collected at an exposure time of 20 seconds / frame. The total data recovery time was 7 hours. The frames were merged, scaled, and merged with the Bruker SAINT software package using a narrow-frame integration algorithm. Integration of data using unconstrained (triclinic) cells resulted in a total of 16473 reflections (24.19 data per average frame) for a maximum angle of? ) Were obtained, of which 8050 were independent. a = 5.78366 (10) Å, b = 14.54887 (23) Å, c = 17.00299 (28) Å, α = 114.9354 (9) °, β = 90.0462 (10) °, γ = 89.9763 (10) °, cell volume = 1297.36 (4) The final cell constant of Å ³ is based on the refinement of 6226 reflections of the XYZ-centroids selected from criteria I > 20σ (I) in the range of 3.09 ° <θ <30.60 °. . Analysis of the data showed negligible decay during data recovery. The data were corrected for absorption effects using multiple scan techniques (SADABS). The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.6022 and 0.7461. Symmetry constrained merge of datasets (monoclinic, space group # 14 in International Tables for Crystallography, Volume A); R _sym = 0.036, R _int = 0.0377, R _sigma = 0.0297] was performed as an XPREP subroutine in the Brewer SHELXTL package. Additional scaling, averaging and statistical processing of reflections is performed by SORTAV code that rejects system-in-system violations, mismatch equivalents, and beam-stop affected reflections by statistical evaluation of the initial dataset (Blessing) algorithm. Structure Bruker SHELXTL (version 6.1.4), the refined using SHELXL-97 codes, such as that run on software packages SIR-92 software (all 18 non-hydrogen atoms were found in its corrected position, R = 7.94%) was solved in the noncentro-symmetrical space group P 2 (1) / n (Z = 4) for the formula unit C ₁₄ H ₁₃ ClN ₂ O. The final anisotropic full-matrix least-squares refinement for F ² with 172 variables (all hydrogen atoms refined except for the methyl group's hydrogen atom) was used for R 1 = 3.10%, converging to wR 2 = 8.27% for all data. Refinement of F ² for all reflections. By weight of the R measurement-factor (in terms of wR) and goodness of fit (goodness of fit) (indicated by S) are conventional R based on F ^2, and - (represented by R) factor, and based on the F, F are And set to 0 for negative F ² . The threshold expression of F ² > 2σ ( F ² ) is used only to calculate the R -factor (gt), etc., and is not related to the selection of refraction reflections. The R - factor based on F ² is statistically about twice as large as that based on F , and the R - factor based on all data will be larger. The fit was 1.043. The maximum peak for the final difference electron density synthesis is 0.40 e ^- / ^{- 3} and the maximum hole is -0.49 e ^- / ^{- 3.} The RMS deviation observed near the Cl 1 atom is 0.05 e ^- / Å ³ and the Fourier It can be regarded as a truncation error (bias) of the difference synthesis. Based on the final model, the calculated density is 1.345 g / cm 3 and F (000) = 552 e ^- .

All estimated standard deviations (denoted as esd) are estimated using a full covariance matrix, except for the standard deviation of the bisector between the two ls planes. Cell esd individually considered in the estimation of esd at distance, angle and twist angle; The correlation between esd in the cell parameter is only used if it is defined by the crystal symmetry. The approximate (isotropic) treatment of the cell esd is used to estimate the esd involving the ls plane.

references

Blessing, R. H. (1987). Cryst. Rev. 1, 3-58.

Blessing, R. H. (1989). J. Appl. Cryst. 22, 396-397.

Bruker (2007). APEX2, SAINT-Plus. Bruker AXS Inc., Madison, Wisconsin, USA.

Bruker (2001). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.

G. & Camalli, M. (1994), Poli-dori, A., Cascarano, G., Giacovazzo, C., Guagliardi, A., Burla, MC. J. Appl. Cryst. 27, 435.

Decision data and structure refinement for sample No. 2 Identification code Sample No. 2 Empirical formula (C ₆ H ₅ ) (CH ₂ ) (NH) (CO) (C ₅ H ₄ N) (CH ₃ ) ⁺ Cl ^- Formula weight 260.72 Temperature 100 (2) K Diffractometer Bruker SMART APEX II Radiation source Fine-focus sealing tube, MoKα Generator power 1250 W (50 kV, 25 mA) Detector distance 40mm Data collection method (Data collection method) ω injection Θ range for data recovery 2.38 to 30.68 wavelength 0.71073Å Variation during data collection (Variation during data collection) Negligible collapse Absorption correction Semi-empirical from equivalents from equivalence Maximum and minimum transmission (Max. And min. Transmission) 0.9 and 0.3449 Crystal system Monoclinic Space group P 2 ₁ / n Unit cell dimensions a = 14.5489 (5) [alpha] = 90 [deg.]
b = 5.7837 (2)?? = 114.935 (2) ?
c = 17.0030 (6) Å γ = 90 ° Volume 1297.38 (8) Å ³ Z 4 Density (calculated value) 1.345 g / cm3 Absorption coefficient 0.28 mm ^-1 F (000) 552 Crystal size 0.10 x 0.10 x 0.10 mm ³ Θ range for data recovery 3.09 to 30.56 Index ranges -20? H? 20 , -8? K? 8, -24? L ? Reflections collected 16473 Independent reflections 2984 [ R (int) = 0.037] Completeness to theta = 27.5 ° for θ = 27.5 ° 99.9% Refinement method Before matrix least square method (Full-matrix least-squares on F 2) for the F ² Structure solution technique Direct method Structure solution program SIR-92 (Sheldrick, 2008) Refinement technique Before matrix least square method (Full-matrix least-squares on F 2) for the F ² Refinement program SHELXL-97 (Sheldrick, 2008) Minimized function (Function minimized) Σ w ( F _o ² - F _c ² ) ² Data / restraints / parameters 2984/0/172 Fit on ^{F 2 (Goodness-of-fit} on F 2) 1.043 Final R indices [ I > 2σ ( I )] R 1 = 0.0310, wR 2 = 0.0784 R indices (all data) R 1 = 0.0405, wR 2 = 0.0828 Maximum difference peak and hole (Largest diff. Peak and hole) 0.402 and -0.390e 占^-3

From a drug formulated as a solid gelatin capsule using two salts of N-methyl-4-benzylcarbamidopyridine, hereinafter referred to as "FAV00A-Cl" and "FAV00A-Io," chloride salts and iodide salts Of active ingredient release profile.

In order to test the rate of FAV00A-Cl release from the finished drug product, three reference drug buffer solutions of pH 1.2, 4.5 and 6.8 and standard measurement conditions (1000 ml of 0.1 M HCl each; 100 rpm (Basque); pH 4.5 Active ingredient release profile studies were performed on 370.6 mg of FAV00A-Cl capsules at 1000 rpm acetate buffer; 100 rpm (Basquette); pH 6.8 phosphate buffer (1000 ml; 100 rpm, Basque). The results of the study were compared again for FAV00A-Io 500 mg capsules (taking into account the molecular weight of FAV00A-Cl and FAV00A-Io substances: the dose of 370.6 mg of FAV00A-Cl substance is equivalent to the dose of 500 mg of FAV00A-Io substance) . The iodide salt FAV00A-Io used in this study was in the α-crystal form of amizone as described in Applicants' co-pending patent applications WO 2011/158058 and WO 2011/157743.

The results are shown in Figs.

For 0.1 M HCl:

At 5 minutes, FAV00A-Cl is released 40% faster than FAV00A-Io;

At 10 minutes, FAV00A-Cl released 20% faster than FAV00A-Io;

For a buffer solution at pH 4.5:

At 5 minutes, FAV00A-Cl is released 25% faster than FAV00A-Io;

At 10 minutes, FAV00A-Cl released 10% faster than FAV00A-Io;

For a buffer solution at pH 6.8:

At 5 minutes, FAV00A-Cl is released 25% faster than FAV00A-Io;

At 10 minutes, FAV00A-Cl is released 15% faster than FAV00A-Io.

CONCLUSIONS: The results of in vitro studies indicate that the release of FAV00A-Cl material from the final finished drug is faster than the FAV00A-Io material in all three reference drug buffer solutions. Release after 15 minutes of FAV00A-Cl material from the final finished drug, including over 85%, can be classified as rapidly dissolving. The faster release of the active ingredient from the medicament also promotes a faster onset of its therapeutic effect.

Claims (17)

A process for preparing N-methyl-4-benzylcarbamamidopyridinium chloride, comprising quaternizing a pyridinium ring atom of benzyl isonicotinic acid with chloromethane according to the following scheme:

The method according to claim 1,
2-propanol, aqueous ethanol and acetonitrile is used. 3. The method according to claim 1 or 2,
RTI ID = 0.0 &gt; 120 C &lt; / RTI &gt; under pressure. 3. The process according to claim 2, wherein the reaction is carried out in acetonitrile while continuing to pass the chloromethane gas through the reaction mixture without being pressurized. The method according to claim 1,
Wherein the reaction time is in the range of 1 to 20 hours. The method according to claim 1,
Wherein the molar ratio between isonicotinic acid benzylamide and chloromethane is in the range of 1 to 1.5. 7. The method according to any one of claims 2, 3 and 6,
Wherein the solvent is 96% ethanol and the reaction is conducted in a pressure range of from 0.1 to 1 MPa (1 to 10 bar), wherein the molar ratio between the isonicotinic acid benzylamide and chloromethane ranges from 1 to 1.5. 8. The method according to any one of claims 1 to 7,
Further comprising recrystallization of the raw product from 96% ethanol. The

Of N-methyl-4-benzylcarbamidopyridinium chloride. 10. The method of claim 9,
N-methyl-4-benzyl carbamidopyridinium chloride containing impurities in the range of less than 0.5%. 11. The method of claim 10,
N-methyl-4-benzylcarbamidopyridinium chloride having a content of isonicotinic acid benzylamide of 0.05% or less. The method according to any one of claims 9 to 11,
N-methyl-4-benzylcarboxamidopyridinium chloride having a melting point in the range of 198 to 203 占 폚. 12. A pharmaceutical composition comprising N-methyl-4-benzylcarbamidopyridinium chloride according to any one of claims 9 to 12. 14. The method of claim 13,
A pharmaceutical composition in the form of a capsule. 15. The method of claim 14,
Wherein the capsule comprises the active ingredient in an amount of 0.01 to 100% by weight. N-methyl-4-benzylcarbamamidopyridinium chloride according to any one of claims 9 to 12 for use in the treatment or prevention of viral diseases and any one of claims 13 to 15 &Lt; / RTI &gt; 17. The method of claim 16,
N-methyl-4-benzylcarboxamidopyridinium chloride and the pharmaceutical composition, wherein said viral disease is an influenza-like disease caused by influenza or respiratory viral infection.

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